The landscape of tolerated genetic variation in humans and primates.

Gao, Hong; Hamp, Tobias; Ede, Jeffrey; Schraiber, Joshua G.; McRae, Jeremy; Singer-Berk, Moriel; Yang, Yanshen; Dietrich, Anastasia S D; Fiziev, Petko P; Kuderna, Lukas F K; Sundaram, Laksshman; Wu, Yibing; Adhikari, Aashish; Field, Yair; Chen, Chen; Batzoglou, Serafim; Aguet, Francois; Lemire, Gabrielle; Reimers, Rebecca; Balick, Daniel; Janiak, Mareike C; Kuhlwilm, Martin; Orkin, Joseph D; Manu, Shivakumara; Valenzuela, Alejandro; Bergman, Juraj; Rousselle, Marjolaine; Silva, Felipe Ennes; Agueda, Lidia; Blanc, Julie; Gut, Marta; de Vries, Dorien; Goodhead, Ian; Harris, R Alan; Raveendran, Muthuswamy; Jensen, Axel; Chuma, Idriss S; Horvath, Julie E; Hvilsom, Christina; Juan, David; Frandsen, Peter; de Melo, Fabiano R; Bertuol, Fabrício; Byrne, Hazel; Sampaio, Iracilda; Farias, Izeni; do Amaral, João Valsecchi; Messias, Mariluce; da Silva, Maria N F; Trivedi, Mihir; Rossi, Rogerio; Hrbek, Tomas; Andriaholinirina, Nicole; Rabarivola, Clément J.; Zaramody, Alphonse; Jolly, Clifford J.;...

Abstract

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.

• Journal Article Type: Article
• Acceptance Date: Mar 22, 2023
• Online Publication Date: Jun 2, 2023
• Publication Date: Jun 2, 2023
• Deposit Date: Jun 7, 2023
• Publicly Available Date: Jun 8, 2023
• Journal: Science (New York, N.Y.)
• Print ISSN: 0036-8075
• Electronic ISSN: 1095-9203
• Publisher: American Association for the Advancement of Science
• Peer Reviewed: Peer Reviewed
• Volume: 380
• Issue: 6648
• DOI: https://doi.org/10.1126/science.abn8197
• Keywords: Animals, Primates - genetics, Whole Genome Sequencing, Humans, Gene Frequency, Genetic Variation, Base Sequence
• Additional Information: “This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on June 2nd 2023 - Volume 380, DOI: https://doi.org/10.1126/science.abn8197